The results of our previous studies with the DES-treated neonatal mouse have revealed an enhanced nuclear retention of estrogen receptor in estrogen target tissues. This and other information suggest a general hypothesis for estrogen-induced carcinogenesis. It is proposed that DES and other estrogens cause permanent changes in estrogen target cells when administered during critical stages of development, and that estrogen-induced alteration of nuclear estrogen receptor retention may be a significant factor contributing to tumorigenesis during estrogen exposure in adult life. Experiments have been designed to: (1) obtain new information on the regulation of estrogen receptor and progesterone receptor ontogeny during postnatal development in the mouse, rat and hamster; (2) identify the permanent alterations in estrogen-receptor and progesterone-receptor systems which result after exposure to DES and other estrogens (estradiol, ethinyl-estradiol, mestranol, transclomiphene, o, p-DDT, coumestrol) during critical times of development; (3) test the hypothesis that DES-induced developmental changes increase the risk of tumor formation during exposure to estrogens later in life; and (4) develop new methods for preventing tumorigenesis based on progesterone and antiestrogen therapy.